Devices and methods for delivery of desired components to a site of interest remain a growing need. A variety of methods and routes of administration have been developed to deliver pharmaceuticals or diagnostics, such as small molecular drugs, imaging agents and/or other biologically active compounds (e.g., peptides, hormones, proteins, and enzymes) and many routes of administration are known for delivering desired pharmaceuticals to a patient. As greater knowledge is learned regarding toxicity of drugs and the ability to elicit specific responses by delivery of a pharmaceutical only to a specific portion of the body, controlled release of pharmaceuticals after their administration has become a highly important area of research.
The therapeutic efficacy of active agents is often limited by the inability to selectively deliver the drugs to the cell. For example, most of the currently available anticancer drugs are highly cytotoxic, and can kill normal cells along with cancerous cells. Thus, when high doses of drugs are used, there can be severe side effects. As a result, most of the currently used anticancer drugs have a rather limited therapeutic index. Such a limit on dosage prevents the complete eradication of cancer cells in a patient, and can lead to recurrence of the cancer in many patients. The limit in dosage can also predispose the recurring cancer to drug resistance, thus worsening the prognosis for the patient. Likewise, the ability to observe selective uptake can lead to selective diagnostics. For example, there is ongoing need for visualizing the delivery of anticancer agents to tumors via various imaging techniques just as much as there is a need for delivering a cocktail of anticancer agents specifically to those tumors.
More generally, technologies which can specifically deliver drugs to affected tissues in diseases involving viral, bacterial, inflammatory, metabolic, and neurologic imbalances represent an important therapeutic breakthrough. Often, therapeutics for these diseases very strictly requires a large therapeutic window to be considered for clinical study. Introduction of moieties which deliver these therapeutics directly and specifically to the diseased tissues or to the disease-causing agents lowers the specificity requirements of the therapeutic itself.
On the surface, antibodies appear to be an ideal coupling partner for therapeutics, helping to deliver them to very specific tissues. However, most antibody-drug conjugates suffer from some drawbacks. In one case, reliable engineering of the attachments is challenging, with only statistical distributions of drugs on the antibody frequently occurring. The potential for cleavage away from the intended target remains with the linker chemistries employed. In another case, the drug is too well attached to the antibody and has trouble either cleaving from the antibody or in escaping from the endosome or lysosome once it is cleaved. The end result is either unwanted systemic toxicity or a lack of efficacy. In addition, the drug or payload may not be cleaved or released in a uniform manner, thereby resulting in a non-uniform distribution of the drug or payload. A technology is sorely needed which allows clean delivery of a uniformly modified antibody to a diseased tissue whereupon the drug is released and permeates the endosome to reach its therapeutic target. Accordingly, there is an ongoing need for new therapeutic approaches that permit the selective delivery of active agents to diseased cells, thereby providing improved therapeutic indices.